CA2044706C - Crystallization method to improve crystal structure and size - Google Patents
Crystallization method to improve crystal structure and size Download PDFInfo
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- CA2044706C CA2044706C CA 2044706 CA2044706A CA2044706C CA 2044706 C CA2044706 C CA 2044706C CA 2044706 CA2044706 CA 2044706 CA 2044706 A CA2044706 A CA 2044706A CA 2044706 C CA2044706 C CA 2044706C
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- 238000002425 crystallisation Methods 0.000 title claims abstract description 47
- 239000013078 crystal Substances 0.000 title claims description 40
- 238000000034 method Methods 0.000 claims abstract description 72
- 230000008569 process Effects 0.000 claims abstract description 54
- 230000008025 crystallization Effects 0.000 claims abstract description 42
- 239000012530 fluid Substances 0.000 claims abstract description 42
- 239000000203 mixture Substances 0.000 claims abstract description 18
- 238000010899 nucleation Methods 0.000 claims abstract description 13
- 230000006911 nucleation Effects 0.000 claims abstract description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 150000001875 compounds Chemical class 0.000 claims description 25
- 239000012296 anti-solvent Substances 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 229910001868 water Inorganic materials 0.000 claims description 17
- 239000012527 feed solution Substances 0.000 claims description 16
- 229960002855 simvastatin Drugs 0.000 claims description 15
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 claims description 14
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 claims description 8
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 claims description 6
- 229960004844 lovastatin Drugs 0.000 claims description 6
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 claims description 6
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 claims description 6
- 229960000583 acetic acid Drugs 0.000 claims description 5
- 229960004039 finasteride Drugs 0.000 claims description 3
- 239000012362 glacial acetic acid Substances 0.000 claims description 3
- 230000009467 reduction Effects 0.000 claims description 3
- 238000010924 continuous production Methods 0.000 claims description 2
- 239000002245 particle Substances 0.000 abstract description 15
- 239000000463 material Substances 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- 238000003801 milling Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- 239000008367 deionised water Substances 0.000 description 6
- 229910021641 deionized water Inorganic materials 0.000 description 6
- 239000007795 chemical reaction product Substances 0.000 description 5
- 230000029087 digestion Effects 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000013019 agitation Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 229940072254 proscar Drugs 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 238000010923 batch production Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000010410 dusting Methods 0.000 description 2
- 238000010316 high energy milling Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- 241000479907 Devia <beetle> Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 238000001016 Ostwald ripening Methods 0.000 description 1
- IUSFTUWHKCSCDY-QTKZZPNDSA-N [(2s,3s)-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl] acetate;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 IUSFTUWHKCSCDY-QTKZZPNDSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229960001758 diltiazem malate Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001746 injection moulding Methods 0.000 description 1
- 229910003480 inorganic solid Inorganic materials 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 238000010903 primary nucleation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010107 reaction injection moulding Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- GCLGEJMYGQKIIW-UHFFFAOYSA-H sodium hexametaphosphate Chemical compound [Na]OP1(=O)OP(=O)(O[Na])OP(=O)(O[Na])OP(=O)(O[Na])OP(=O)(O[Na])OP(=O)(O[Na])O1 GCLGEJMYGQKIIW-UHFFFAOYSA-H 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000028016 temperature homeostasis Effects 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/0004—Crystallisation cooling by heat exchange
- B01D9/0009—Crystallisation cooling by heat exchange by direct heat exchange with added cooling fluid
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/0018—Evaporation of components of the mixture to be separated
- B01D9/0027—Evaporation of components of the mixture to be separated by means of conveying fluid, e.g. spray-crystallisation
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
- B01F25/20—Jet mixers, i.e. mixers using high-speed fluid streams
- B01F25/23—Mixing by intersecting jets
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F33/00—Other mixers; Mixing plants; Combinations of mixers
- B01F33/30—Micromixers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T137/00—Fluid handling
- Y10T137/8593—Systems
- Y10T137/87571—Multiple inlet with single outlet
- Y10T137/87652—With means to promote mixing or combining of plural fluids
Landscapes
- Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Physics & Mathematics (AREA)
- Thermal Sciences (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Crystals, And After-Treatments Of Crystals (AREA)
- Pyrane Compounds (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
- Physical Or Chemical Processes And Apparatus (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Impinging fluid jet streams are used in a continuous crystallization process to achieve high intensity micromixing of fluids so as to form a homogeneous composition prior to the start of nucleation. This process permits direct crystallization of high surface area particles of high purity and stability.
Description
TITLE OF THE INVENTION
A CRYSTALLIZATION METHOD TO IMPROVE CRYSTAL STRUCTURE AND
SIZE
BACKGROUND OF THE INVENTION
Crystallization from solution of pharmaceutically active compounds or their intermediates is the typical mf=thod of purification used in industry. The integrity of the crystal structure, or crystal habit, that is produced and the particle size of the end product are importa-nt considerations in the crystallization process.
High bioavailability and shoat dissolution time are desirable or often necessary attributes of the pharmaceutical end product. However, the direct crystallization of small sized, high surface area particles is usually accomplished in a high supersaturation environment which often results in material of low purity, high friability, and decreased stability due to poor crystal structure formation. because the bonding forces in organic to crystal lattices generate a much higher frequency of amorphism than those found in highly ionic inorganic solids, "oiling out" of supersaturated material is not uncommon, and such oils often solidify without structure.
Slow crystallization is a common technique used to increase product purity and produce a more stable crystal structure, but it is a prace:ss that decreases crystallizer productivity and produces large, low surface area particles that require subsequent high 2o intensity milling. Currently, pharmaceutical compounds almost always require a post-crystallization milling step to increase particle surface area and thereby improve their bioavailability. However, high energy milling has drawbacks. Milling may result in 25 yield loss, noise and dusting, as well as unwanted personnel exposure to highly potent pharmaceutical compounds. ~.lso, stresses generated on crystal surfaces during milling can adversely affect labile compounds. Overall, the three most desirable 3o end-product goals of high surf ace area, high chemical purity, and high stability cannot be optimized simultaneously using current crystallization technology without high energy milling.
One standard crystallization procedure involves contacting a supersaturated solution of the compound to be crystallized with an appropriate "anti-solvent" in a si~irred vessel. Within the stirred vessel, the anti-solvent initiates primary nucleation which leads to crystal formation, sometimes with the help of seeding, and crystal digestion during an aging step. Mixing within the vessel can be achieved with a variety of agitators (e. g., Rushton (Trade-mark) or pitched blade turbines, Intermig (Trade-mark), etc.), and the process is dor_e in a batchwise fashion.
When using current reverse addition technology for direct small partic=Le crystallization, a concentration gradient can not be avoided during initial crystal formation because the introduction of feed solution to anti-solvent in the stirred vessel does not afford a.
thorough mixing of the two fluids prior to crystal formation. The existence of concentration gradients, and therefore a heterogeneous fluid environment at the point of initial crystal formation, impedes optimum crystal structure formation and increases impurity entrainment.
If a slow crystallization technique is employed, more thorough mixing of the fluids can be attained prior to crystal formation which will improve crystal structure and purity, but the crystals produced will be large and milling will be necessary to meet bioavailability requirements.
Another standard crystallization procedure employs temperature variation of a solution of the ~~~~~''~~~~
79/CS~28 - 4 - 18128IA
material to be crystallized in order to bring the solution to its supersaturation point, but this is a slow process that produces large crystals. Also, despite the elimination of a solvent gradient with this procedure, the resulting crystal characteristics ' of size, purity and stability are difficult to control and are inconsistent from batch to batch.
The novel process of this invention utilizes impinging jets to achieve high intensity micromixin,g in the crystallization process. High intensity micromixing is a well known technique where mixing-dependent reactions are involved. Feeding strategies as they relate to precipitation were addressed by Mersmann, A. and Kind, M., ~,~micat ~5 Engxn~erin~ As~~~;s of Frecipita iron from Solution, Chem. Eng. Technol., V. 11, p. 264 (1988). Notable among other papers recently addressing the effect of micromixing in reaction processes are Garside, J. and ~avare, N. S., ~iXin . ~teaction and P~ ecxpxt~~in"~
20 , ss~ tallizer, Chem.
Eng. Sci., V. 40, p. 1485 (1985); Pohorecki, R. and Baldyga, J. , The 'Use of a IVew Model of Micromixing for Determinat~.on gf Crystal Size in i'recipitation, Chem. Eng. Sci., V. 38, p. 79 (1983). However, the 25 use of high intensity micromixing is not the norm in current crystallization technology where no chemical reaction is involved.
Tmpinging jets are used for micromixing routinely in reaction injection moulding (ItIM) 3o technology in the plastics industry but not for the purpose of causing crystallization. The use of an impinging jet device in a crystallization process to 79/CSQ2S - 5 -- 1812~IA
achieve intense micromixing is novel. tahether feed material is relatively pure or impure, the use of impinging jets results in crystal characteristics superior to those that result from standard crystallization methods.
Now with the present invention there is provided a method f or crystallization of pharma-ceutical compounds or their intermediates which directly produces high surface area end product crystals with greatly improved stability and purity and thereby eliminates the need for subsequent high intensity milling to meet bioavailability require-ments. By removing the need for milling, the novel jet process avoids associated problems of noise and dusting, cuts yield loss, and saves the time and extra expense incurred during milling. It also removes an extra opportunity f or personnel contact with a highly potent pharmaceutical agent, or f or adverse effects on labile compaunds. The small particle size attained with the jet process is consistent within a single run and as shown in Table 1, results are reproducible between runs. Reproduci-bility is an attribute of this process that is not common to °~reverse addition" methods typically used to produce small crystals.
The pure, high surface area particles that result from the jet process also display superior crystal structure when compared to particles formed via standard slow crystallization plus milling 3o methods using the same quality and kind of feed compound. Improvements in crystal structure result in decreases in decomgosition rate and therefore 79/CSQ28 - 6 - 18128I~A
longer shelf-lif a f or the crystallized product or a pharmaceutical composition containing the crystallized material. As shown in Table 29 the material produced by the jet process exhibits more consistent accelerated stability results than that produced by the conventional batch process.
The purity of crystallized material produced from the jet process is superior to that from standard reverse addition direct small particle crystallization, as demonstrated with simvastatin using high performance liquid chromatography ~~pLC, in Table 3. Standard slow batch crystallization affords product purity comparable to that afforded by the jet process, but the jet process is superior because9 as noted above, in addition to high purity, it also provides higher quality crystal habit and increased particle surface area thereby eliminating the need for milling.
Jet process crystallization is suited for continuous processing. Standard crystallization methods are generally run in a batchwise fashion.
Continuous processing affords two advantages. first, the same amount of feed compound can be crystallized in significantly less volume via continuous processing than would be possible using a batch by batch method. Second, continuous processing enhances reproducibility of results because all the material crystallizes under uniform conditions. Such uniformity is not possible using batch methods in which concentration, solubility and other parameters change with time.
7~/csQaB - ~ - ~siaszA
~~x cRx~~~,~,~xz~~ s~rrv~s~~T~N
~ Surface Area (m~/g) at 45~ 5°C
3.37*
a 2.57*
3 2.88*
4 3.56*
IO 5 3.35 a.55 Mean:' 3.05 ~,~ndard Devia'tiow _- 0.40 *Run at 50-5~.°C.
l9lCSQ28 - 8 - 18128IA
ELERA ST T
SET-C RYSTALLIZEp SIMVASTATIN
Surface4deeks C) (at Bateh Area~,_,~ .~ .~, ~ ~ ~ ~cuo C
1 2.4 98.7 96.895.1 97.2 68 99.4 2 4.Q 98.9 93.398.1 95.1 55 92.5 3 5.5 99.3 88.593.4 85.7 55 96.5 4 4.6 98.8 96.486.0 8D.1 55 95.1 SLOW qTCHCRYSTALLI~FD~IMVASTATINMILI~ED) B L
_ 1 5 3.098.8 95.595.795.0 95.0 *
2 3.399.1 94.994.383.6 95.0 . *
3 2.699.0 98.295.993.0 93.5 4 2.799.2 98.495.395.A 82.8 *
99.7 98.398.081.3 36.6 *
~ 0 99 2 94 8~Q 77.8 34. 0 *
* Heat-cool process used.
Simvastatin HPLC 969 Crystallization Temp. Purity Impurity**
l~etho~* _~.Ca _(~h~~o~ (Weight ~e~
Continuous l0 Impinging Jets 50 99.0 <0.1 Continous Impinging Jets 25 98.6-99.0 0.2-0.4 ~5 Batch Reverse Addition 25 98.7 0.7 Slow Batch Process 99.0 <0.1 20 Product Specification>98.5 <0.5 * 50:50 Volumetric ratio og Me0H:H20 used with impinging jet method; final volumetric ratio of 50:50 Me0H:H20 used with reverse addition and slow batch methods.
** Open ring form of simvastatin.
~~~~'~~~
79lCSQ28 - 10 - W128za Y o~ T~z~ zNVENTZON
This invention concerns a process for crystallization.
More particularly, this invention relates to the use of impinging jets to achieve high intensity micromixing of fluids so as to form a homogeneous composition prior to the start of nucleation in a continuous crystallization process.
Nucleation and precipitation can be initiated by Io utilizing_the effect of temperature reduction on the solubility of the compound to be crystallized in a particular solvent (thermoregulation), or by taking advantage of the solubility characteristics of the compound in solvent mixtures, or by some combination of the two techniques.
The novel process of this invention provides for the direct crystallization of high surface area particles of high purity and stability.
20 ERIEF DESCRIPTION of TF_iE DRAWINGS
Two embodiments of the invention have been chosen for purposes of illustration and description, and are shown in the accompanying drawings forming a part of the specification wherein:
FIG. 1 is a schematic diagram showing a crystal production system depicting the jet chamber 3, the transfer line 4, the stirxed vessel 5, the agitation device 6 and the entry point of two fluids 1 and 2 into the system;
30 Fig. 2 is an enlarged sectional view of jet chamber 3 showing an arrangement for impinging jet introduction of two fluids inta the system;
79/CSg28 - 11 - 18128IA
FzG. 3 is an overhead view of the jet chamber 3;
~'I~. 4 shows particle surface area as a function of supersaturation ratio using the jet crystallization process with simvastatin; and FIG. 5 is a schematic diagram showing a crystal production system depicting two fluids, 11 and 12, entering directly into the stirred vessel 13 containing liquid 14 (the liquid being solvent and/or anti°solvent) where the jets 16 emit fluid jetstreams that impinge and micromix near the effluent stream of the impeller 15.
~n n~SC~z~TZO~a of TH~ zrrv~rrTZO~
The novel process of this invention involves the use of jets to create impinging fluid jet streams and thereby achieve high intensity micaomixing of the fluids prior to nucleation in a crystallization process. Two or more jets may be used to micromix two or more fluids. Preferably, two jets are used to micromix two fluids. 6~hen using two jets, preferably the two impinging jet streams should be substantially diametrically opposed to each other, i.e., they should be at or close to a 180 degree angle to each other from an overhead view. FTG. 1 shows one ennbodiment of this invention wherein two jets are employed; fluids 1 ~a~d 2 enter the jet chamber 3 where micromixing takes place. F'IC 5, shows another embodiment of this invention, wherein ~
jets are employed and the jetstreams impinge and F~
~a/csQzs - 12 - 18x2~zA
micromi~c directly in the stirred vessel 13. As used herein, the terms stirred vessel and age vessel have the same meaning and axe interchangeable.
The two fluids used in the novel process of this invention can be of different solvent composition, one fluid being a solution of the compound to be crystallized in a suitable solvent or combination of solvents ('°feed solution"), and 'the other fluid being a suitable solvent or combination of solvents capable of initiating that compound's precipitation from solution ('°anti-solvent"), chosen for its relatively low solvation property with respect to that compound. Such solvents and anti-solvents can include but are not limited to methanol, ethyl acetate, halogenated solvents such as methylene chloride, acetonitrile, acetic acid, hexanes, ethers, and water.
Or, the two fluids used in the process can both be solutions of the compound to be crystallized 2o in the same suitable solvent or combination of solvents but each at a different temperature, and nucleation/precipitation can be initiated by instantaneous temperature reduction. The temperature and composition of each solution are chosen so that 1) no material will crystallize upstream of the impinging jets, and 2) sufficient supersaturation will be developed in the impinging jets to cause nucleation. ~Iicrom~.~ing creates temperature and compositional uniformity throughout the mixture prior to the start of nucleation.
The following is a list of compounds that have been successfully crystallized to meet particle size and purit=y specifications using the present invention: simvastatin, lovastatin (crude and pure), Proscar (Trade-mark for finasteride containing pharmaceutical composition) diltiazem malate, 173-benzoyl-4-aza-5a-androst-1-ene-3-one, 4"-epi--ac etylamino-avermectin B1, [trans-(-)]-2-[(3-methoxy-2-propoxy-5-- [tetrahydro-5- (3, 4, 5-trimethoxyphenyl) -2-furanyl] phenyl] -sulfonyl] -ethanol (DevLab, England) . However, this is not. an exhaustive list of all the compounds that can be used with the present invention.
After micromixang in a jet chamber, the material leaves the jet chamber as depicted in Fig. 1, travels into a stirred vessel 5 either directly or via a transfer lane 4, and after an appropriate age time, the product suspension flows out of the vessel as indicated by arrow A. Another embodiment of this invention involves the micromixing of two impinging jetstreams directly in the stirred vessel without the use of a jet chamber or transfer line, as depicted in FIG. 5. For the crystal-lization of simvastatin, the preferred method is for two jetstreams to impinge directly in the starred vessel. Once the material leaves the stirred vessel, appropriate recovery techniquE>_s are used to isolate the product crystals. The material preferably flows through the system in a continuous process, although it is possible to hold up the process in a batchwise fashion at the stirred vessel-aging step given a vessel of sufficient volume.
As shown in FIG. 2 and FIG. 3, the jet chamber 3 is preferably cylindrical in shape and as shown in FIG. 2 the jet chamber 3 preferably has a floor l0 which slopes downward in a conical shape toward the flooros center which is open to a connecting transfer line 4 or directly into a stirred vessel or other appropriate container. The diameter and cylinder wall height of the chamber can vary according to scale needs.
Regardless of the number of jets used, the jet nozzles should be placed so that the fluid streams they emit will impinge, either inside the jet chamber ox directly in the stirred vessel. The fluid jets must impinge to create an immediate high turbulence impact; concentric or converging jets generally create insufficient turbulence to achieve the required micromixing. When two jets are used with a jet chamber, as shown in PTG. 2 and PIG. 3, the two jet nozzles 7 are preferably arranged so that they are substantially diametrically opposed to each other with their outlet taps directed to face each other; i.e., the two jet nozzles are at or close 'to a 18~ degree angle to each other from an overhead view. Preferably, each jet outlet nozzle can have a slight downward angle from the horizontal of about 1Q
degrees to help the flowing material move down and out of the chamber.
~5 hikewise, two jet nozzles placed directly inside the stirred vessel are preferably arranged so that they are substantially diametrically opposed to each other with their outlet tips directed to fat's each other. When the jet nozzles are so placed, each nozzle can have a slight upward or downward angle from the horizontal of from 0 degrees up to about 15 degrees, but preferably the two nozzles have just a~~~~
enough downward angle from the horizontal (~. 13 degrees) to ensure that the fluid stream of one will not enter the outlet hole of the opposite nozzle.
One jet nozzle is used to transport one of the two fluids from an external source into the chamber and the other jet is used to similarly transport the other fluid. The distance between the nozzle tips inside the jet chamber or stirred vessel should be such that the hydrodynamic form of each a0 fluid jet stream remains essentially intact up to the point of impingement. Therefore, the maximum distance between the nozzle tips wall vary depending on the linear velocity of the fluids inside the jet nozzles. To obtain good results for generally non-viscous fluids, linear velocity in the jet nozzles should be at least about 5 meters/sec., more preferably above 10 meters/sec., and most preferably between about 20 to 25 meters/sec., although the upper limit of linear velocity is only limited by the practical difficulties involved in achieving i~t.
Linear velocity and flow rate can both be controlled by various known methods, such as altering the diameter of the entry tube 8 and/or that of the nozzle outlet tip 9, and/or varying the strength of the external force that moves the fluid into and through the nozzle. Each jet apparatus can be manipulated independently to attain a desired final fluid composition ratio. 4Jhen the desired flow ratio of one jet to the other differs from unity, preferably the difference is compensated for by appropriate sizing of the entry tubes. For example, if a 4:1 volumetric ratio of feed solution to 1~
'79/C5Q28 -- 16 - 18128I~
anti-solvent is desired, the entry tube delivering feed solution should be twice the diameter of the entry tube delivering anti-solvent. tdhen the jetstreams impinge inside a jet chamber, residence time for the fluid inside the jet chamber is typically very short, i.e., less than ten seconds.
A transfer line 4 as shown in FIG. 1 may or may not be used to deliver the fluid mixture into a stirred vessel 5 from the jet chamber. Solvent, anti--solvent or mixtures thereof optionally containing seed and optionally heated to attain optimum crystallization results can be put inside the stirred vessel FIG. 1 (5), FIG. 5 (13) at the start of the process before the micromixed fluids enter the stirred vessel; this technique is especially preferred when the jetstreams impinge directly in the stirred vessel. Crystal digestion (ostwald ripening, improvement of surface structure) tales place inside the stirred vessel.
2o Stirring in the vessel is provided by standard agitators 6, preferably Rushton turbines, Intermig impellers, or other agitators suitable for stirring a slurry suspension. Any impeller providing good circulation inside the vessel may be used.
Rowever, when the jetstreams are arranged to impinge directly inside the stirred vessel, an agitator that does not interfere with the space occupied by the impinging jetstreams inside the vessel is preferred, especially, e.g., a Rushton turbine. As depicted in 3o FIG. 5, impinging jetstreams inside the vessel are most preferably placed in the effluent stream of the agitator, and the height of the liquid in the stirred vessel when operated in continuous mode (i.e., flow in equals flow out, constant volume maintained), is most preferably between about two to four times the height of tlZe impeller.
The crystalliz<~tion is preferably run in a con-t:inuous process and the appropriate residence time for the completion of crystal digestion is attained by adjusting the volume capacity of the stirred vessel, but the mixture can be held up in the vessel for any desired length of age time if batchwise processing is desired.
For example, during simvastatin crystallization crystal digestion is complete within about 5 minutes and a vessel volume of roughly 5 liters is sufficient for a residence t=ime of 5 minutes with a material flow of about 1 liter per minute. Finasteride (Proscar) is similar to simvastatin with respect to age time. In some instances when the fluids impinge and micromix inside a jet chamber, crystallization conditions may be optimized so that crystal precipitation and growth are completed w=ithin the transfer line itself, or even before entering the transfer line, and the crystals may be directly collected, bypassing any age time in the stirred vessel.
Manual seeding can be done at any point in the system, e.g., in the stirred-vessel, the transfer line or the jet chamber itself. In some situations" the continuous jet process may be "self-seeding", i.e., the first crystals to form inside the jet chamber (if used), the transfer line (if used) or the stirred vessel (if used) serve as seed for the material that flows through thereafter.
P
The micromixed material must be highly supersaturated to attain the beneficial results of the jet crystallization process. Aside from thermoregulated initiation of nucleation, temperature variation also affects product results when anti-solvent is used to initiate nucleation because of its effect on supersaturation. Generally, good results can be achieved for pharmaceutical compounds using a volumetric ratio of feed solution to la anti-solvent that pravides a high degree of supersatuzation in the jet chamber in a temperature range of about 24°C to 70°C, although temperature height is limited only by the chosen solvent's boiling point and the compound's decomposition range. Temperatures above ambient may give improved product characteristics. As an exacnple, optimum results with regard to end product ~>urface area, purity and stability are achieved for simvastatin by xunning the crystallization at an e7levated 2~ temperature of at least 55°C, more preferably in the range of 60 to 70°C, and most preferably at 65 to 68°C, in a 41:59 volumetric mixture of Me0H:H2Q. In this case, the composition in the impinging jetstreams is 50:50 Me0H:H2a, and the composition in 2~ the age 'tank is brought to 41:59 MedH:H~O by a separate, additional water injection (nat through the impinging jet) directly into the stirred vessel. ~
75:25 volumetric mixture of Me0H:H20 used at room temperature produces crystals essentially the same as those from conventional batchwise crystallization, i.e, they require milling. A 41:59 volumetric mi~cture of Me0H:H20 used at room temperature results in particles with average surface area above the desirable range and decreased purity as shown in FIG. 4.
Ambient temperature (room temperature) operation using the jet process provides sufficiently good re:~ults for finasteride (Proscar) and therefore elevated temperatures are not necessary.
A temperature of 40 to 58°C using the jet process is suitable for lovastatin.
The following examples are given for the purpose of illustrating the present invention and should not be construed as limitations on the scope or spirit of t:he instant invention.
EXAMPLE I
Crystallization of Einasteride (Proscar) 100 Grams of Proscar was dissolved in 600 ml. of glacial acetic acid; once dissolution was complete, 400 ml.
deionized water was added (i.e., a 60:40 volumetric ratio of glacial acetic acid: water). The solution was filtered a;~ 1 litre of feed solution through a 0.2 micron membrane into a blow can. The blow can outlet was connected to a 1/16 in. OD jet nozzle (0.052 in. ID). 5.5 Liters of deionized water was filtered as anti-solvent througr, a 0.2 micron membrane into a second blow can, and its outlet connected to a 1/8 in. OD jet nozzle (0.0938 in.
ID). This provides a 1:5.5 volumetric ratio of feed solution:anti-solvent. Each blow can was pressurized to - 19a -ca. 90 psi with regulated nitrogen. The impinging jets were started simultaneously. The desired flow rate of the acetic acid solution was 0.2 gpm (linear velocity ca. 550 meters/min:) and the desired flow rate of 100% H20 was 1.1 gpm (linear velocity ca. 930 meters/min.). The effluent slurry was collected from the mixing chamber in a 12L
round-bottom flask equipped with a paddle agitator. A
minimum age time of two minutes was required to complete crystal digestion. 'rhe solids were filtered, water washed, then dried.
Crystals were 10 to 20 microns in diameter and 1 micron thick, in the form of flakes; specification is 950 <:
smaller than 25 microns.
Crystallization of Simvastatin 100 Grams of s:imvastatin were dissolved in 1400 ml.
methanol, and the solution heated to approximately 550C.
Deionized water (1400 ml.) was heated to approximately 55°C. The heated water was fed to one blow can and the heated methanol solution was fed to a second blow ca.n.
Each blow can outlet was connected to a lmm. ID jet nozzle. Each blow can was pressurized to 25-35 psi, and impinging jets were started simultaneously. The flow from each jet was 1.1 liter/min. (linear velocity ca. 23 meters/sec.).
The jet chamber was approximately 2 inches in diameter and I inch high with a conical bottom outlet. Effluent from this chamber was directed to a 4 liter beaker (approx. 6 inches diameter). The beaker contained 2.5 grams simvastatin seed (dry surface area 2.5 to 6 sq:
m/gm), and was agitated at 300 "M by three Ekato Intermig (Trade-mark) impel:Lers, each 3.5 inches in diameter. When the cans were empty (75 seconds), they were vented. Aging (agitation at 300 RPM, no cooling) took place in the beaker for 5 to 20 minutes. The contents were then cooled with the ;~~~'~'~~~
same agitation to less than 30°C by immersion in an ice bath. Contents were then filtered and tray dried (~0°C at 28-30 in. Eg vacuum with slight nitrogen sweep) for 12 to 16 hours.
The resultant dry solid (88-99 grams) had a surface area of 3.1 ~/° 0.~ square meters per gram. Mother liquor losses were 1-2°~, the remaining yield being held up in the apparatus. product could be used to seed future batches without further 1~ treatment.
~XAI~IpLE ~ , Crvstallizati~n c~f 'mv statin, 68-68°C
The crystallization of example 2, with the following modifications:
(1) temperature in the jet impingement zone and in the 5 to 20 minute age was raised to 86-68°C, 2~ by preheating the methanol feed solution to 55°C and the water feed to 85°C; and (2) final age tank solvent composition was reduced to 41°/ methanol by suspension of the initial 2W gram seed charge in 600 m1 deionized water at 70°C.
the final product was similar in particle size, surface area and appearance to the product from sample 2. aowever; storage stability (60°C) was improved from very good (F~cample 2) to outstanding (Example 3), implying a higher order of crystallinity.
Crystallization of.-Simvastatin, Immersed jets The crystallization of Example 3, with the modification that the impinging jets-were submerged,.
without containment, inside the agitated age vessel near the effluent stream of the impeller. To accommodate the immersed jets, a 6-liter baffled battery jar (cylindrical), 8-1/4 inches in diameter and 10 inches high, was agitated by a 3 inch diameter Rushton turbine.
T:he impinging jets were located near the horizontal plane of the impeller, I to 2 inches from the impeller's outer edge.
The final product was essentially identical with that of Example 3. Caking of amorphous solid on the wall of the jet chamber, which occurs in extended runs in Examples 2 and 3, was eliminated because there was no containment wall around the jets.
Crystallization of Lovastatin 38.0 Grams of lovastatin were added to 1260 ml methanol and 140 ml deionized water (i.e. 90:10 volumetric ratio o:f methanol t.o water). The mixture was heated to 55°C with agitation (magnetic stirrer in closed Erlenmeyer flask). Activated carbon (12.78, Calgon type APA 12x40 - Calgon .is a Trade-mark) was added, the mixture stirred at 55°C and hot filtered. The filtrate was reheated to 55°C (when necessary) and added quickly to a blow can attached to one impinging jet device nozzle (1.0 mm diameter) as feed solution. 538 Milliliters of 60°C deionized water (anti-solvent) was added to another blow can connected to the opposing jet (0.5 mm diameter). Both cans were pressurized to 25-30 psig and the liquids fed to the respective jets, completed in 1 minute, 45 seconds (i.e., a 2.6:1 volumetric ratio of feed solution:anti-solvent). The agitated beaker (same as Example 1) was aged at the jet outlet temperature (43°C) for 5 minutes, cooled with stirring to less than 30°C, and filtered and dried.
The final product was fine needles with acceptable surface area 1.6m2/gm. Purity was equal to that from.
conventional seeded crystallization.
A CRYSTALLIZATION METHOD TO IMPROVE CRYSTAL STRUCTURE AND
SIZE
BACKGROUND OF THE INVENTION
Crystallization from solution of pharmaceutically active compounds or their intermediates is the typical mf=thod of purification used in industry. The integrity of the crystal structure, or crystal habit, that is produced and the particle size of the end product are importa-nt considerations in the crystallization process.
High bioavailability and shoat dissolution time are desirable or often necessary attributes of the pharmaceutical end product. However, the direct crystallization of small sized, high surface area particles is usually accomplished in a high supersaturation environment which often results in material of low purity, high friability, and decreased stability due to poor crystal structure formation. because the bonding forces in organic to crystal lattices generate a much higher frequency of amorphism than those found in highly ionic inorganic solids, "oiling out" of supersaturated material is not uncommon, and such oils often solidify without structure.
Slow crystallization is a common technique used to increase product purity and produce a more stable crystal structure, but it is a prace:ss that decreases crystallizer productivity and produces large, low surface area particles that require subsequent high 2o intensity milling. Currently, pharmaceutical compounds almost always require a post-crystallization milling step to increase particle surface area and thereby improve their bioavailability. However, high energy milling has drawbacks. Milling may result in 25 yield loss, noise and dusting, as well as unwanted personnel exposure to highly potent pharmaceutical compounds. ~.lso, stresses generated on crystal surfaces during milling can adversely affect labile compounds. Overall, the three most desirable 3o end-product goals of high surf ace area, high chemical purity, and high stability cannot be optimized simultaneously using current crystallization technology without high energy milling.
One standard crystallization procedure involves contacting a supersaturated solution of the compound to be crystallized with an appropriate "anti-solvent" in a si~irred vessel. Within the stirred vessel, the anti-solvent initiates primary nucleation which leads to crystal formation, sometimes with the help of seeding, and crystal digestion during an aging step. Mixing within the vessel can be achieved with a variety of agitators (e. g., Rushton (Trade-mark) or pitched blade turbines, Intermig (Trade-mark), etc.), and the process is dor_e in a batchwise fashion.
When using current reverse addition technology for direct small partic=Le crystallization, a concentration gradient can not be avoided during initial crystal formation because the introduction of feed solution to anti-solvent in the stirred vessel does not afford a.
thorough mixing of the two fluids prior to crystal formation. The existence of concentration gradients, and therefore a heterogeneous fluid environment at the point of initial crystal formation, impedes optimum crystal structure formation and increases impurity entrainment.
If a slow crystallization technique is employed, more thorough mixing of the fluids can be attained prior to crystal formation which will improve crystal structure and purity, but the crystals produced will be large and milling will be necessary to meet bioavailability requirements.
Another standard crystallization procedure employs temperature variation of a solution of the ~~~~~''~~~~
79/CS~28 - 4 - 18128IA
material to be crystallized in order to bring the solution to its supersaturation point, but this is a slow process that produces large crystals. Also, despite the elimination of a solvent gradient with this procedure, the resulting crystal characteristics ' of size, purity and stability are difficult to control and are inconsistent from batch to batch.
The novel process of this invention utilizes impinging jets to achieve high intensity micromixin,g in the crystallization process. High intensity micromixing is a well known technique where mixing-dependent reactions are involved. Feeding strategies as they relate to precipitation were addressed by Mersmann, A. and Kind, M., ~,~micat ~5 Engxn~erin~ As~~~;s of Frecipita iron from Solution, Chem. Eng. Technol., V. 11, p. 264 (1988). Notable among other papers recently addressing the effect of micromixing in reaction processes are Garside, J. and ~avare, N. S., ~iXin . ~teaction and P~ ecxpxt~~in"~
20 , ss~ tallizer, Chem.
Eng. Sci., V. 40, p. 1485 (1985); Pohorecki, R. and Baldyga, J. , The 'Use of a IVew Model of Micromixing for Determinat~.on gf Crystal Size in i'recipitation, Chem. Eng. Sci., V. 38, p. 79 (1983). However, the 25 use of high intensity micromixing is not the norm in current crystallization technology where no chemical reaction is involved.
Tmpinging jets are used for micromixing routinely in reaction injection moulding (ItIM) 3o technology in the plastics industry but not for the purpose of causing crystallization. The use of an impinging jet device in a crystallization process to 79/CSQ2S - 5 -- 1812~IA
achieve intense micromixing is novel. tahether feed material is relatively pure or impure, the use of impinging jets results in crystal characteristics superior to those that result from standard crystallization methods.
Now with the present invention there is provided a method f or crystallization of pharma-ceutical compounds or their intermediates which directly produces high surface area end product crystals with greatly improved stability and purity and thereby eliminates the need for subsequent high intensity milling to meet bioavailability require-ments. By removing the need for milling, the novel jet process avoids associated problems of noise and dusting, cuts yield loss, and saves the time and extra expense incurred during milling. It also removes an extra opportunity f or personnel contact with a highly potent pharmaceutical agent, or f or adverse effects on labile compaunds. The small particle size attained with the jet process is consistent within a single run and as shown in Table 1, results are reproducible between runs. Reproduci-bility is an attribute of this process that is not common to °~reverse addition" methods typically used to produce small crystals.
The pure, high surface area particles that result from the jet process also display superior crystal structure when compared to particles formed via standard slow crystallization plus milling 3o methods using the same quality and kind of feed compound. Improvements in crystal structure result in decreases in decomgosition rate and therefore 79/CSQ28 - 6 - 18128I~A
longer shelf-lif a f or the crystallized product or a pharmaceutical composition containing the crystallized material. As shown in Table 29 the material produced by the jet process exhibits more consistent accelerated stability results than that produced by the conventional batch process.
The purity of crystallized material produced from the jet process is superior to that from standard reverse addition direct small particle crystallization, as demonstrated with simvastatin using high performance liquid chromatography ~~pLC, in Table 3. Standard slow batch crystallization affords product purity comparable to that afforded by the jet process, but the jet process is superior because9 as noted above, in addition to high purity, it also provides higher quality crystal habit and increased particle surface area thereby eliminating the need for milling.
Jet process crystallization is suited for continuous processing. Standard crystallization methods are generally run in a batchwise fashion.
Continuous processing affords two advantages. first, the same amount of feed compound can be crystallized in significantly less volume via continuous processing than would be possible using a batch by batch method. Second, continuous processing enhances reproducibility of results because all the material crystallizes under uniform conditions. Such uniformity is not possible using batch methods in which concentration, solubility and other parameters change with time.
7~/csQaB - ~ - ~siaszA
~~x cRx~~~,~,~xz~~ s~rrv~s~~T~N
~ Surface Area (m~/g) at 45~ 5°C
3.37*
a 2.57*
3 2.88*
4 3.56*
IO 5 3.35 a.55 Mean:' 3.05 ~,~ndard Devia'tiow _- 0.40 *Run at 50-5~.°C.
l9lCSQ28 - 8 - 18128IA
ELERA ST T
SET-C RYSTALLIZEp SIMVASTATIN
Surface4deeks C) (at Bateh Area~,_,~ .~ .~, ~ ~ ~ ~cuo C
1 2.4 98.7 96.895.1 97.2 68 99.4 2 4.Q 98.9 93.398.1 95.1 55 92.5 3 5.5 99.3 88.593.4 85.7 55 96.5 4 4.6 98.8 96.486.0 8D.1 55 95.1 SLOW qTCHCRYSTALLI~FD~IMVASTATINMILI~ED) B L
_ 1 5 3.098.8 95.595.795.0 95.0 *
2 3.399.1 94.994.383.6 95.0 . *
3 2.699.0 98.295.993.0 93.5 4 2.799.2 98.495.395.A 82.8 *
99.7 98.398.081.3 36.6 *
~ 0 99 2 94 8~Q 77.8 34. 0 *
* Heat-cool process used.
Simvastatin HPLC 969 Crystallization Temp. Purity Impurity**
l~etho~* _~.Ca _(~h~~o~ (Weight ~e~
Continuous l0 Impinging Jets 50 99.0 <0.1 Continous Impinging Jets 25 98.6-99.0 0.2-0.4 ~5 Batch Reverse Addition 25 98.7 0.7 Slow Batch Process 99.0 <0.1 20 Product Specification>98.5 <0.5 * 50:50 Volumetric ratio og Me0H:H20 used with impinging jet method; final volumetric ratio of 50:50 Me0H:H20 used with reverse addition and slow batch methods.
** Open ring form of simvastatin.
~~~~'~~~
79lCSQ28 - 10 - W128za Y o~ T~z~ zNVENTZON
This invention concerns a process for crystallization.
More particularly, this invention relates to the use of impinging jets to achieve high intensity micromixing of fluids so as to form a homogeneous composition prior to the start of nucleation in a continuous crystallization process.
Nucleation and precipitation can be initiated by Io utilizing_the effect of temperature reduction on the solubility of the compound to be crystallized in a particular solvent (thermoregulation), or by taking advantage of the solubility characteristics of the compound in solvent mixtures, or by some combination of the two techniques.
The novel process of this invention provides for the direct crystallization of high surface area particles of high purity and stability.
20 ERIEF DESCRIPTION of TF_iE DRAWINGS
Two embodiments of the invention have been chosen for purposes of illustration and description, and are shown in the accompanying drawings forming a part of the specification wherein:
FIG. 1 is a schematic diagram showing a crystal production system depicting the jet chamber 3, the transfer line 4, the stirxed vessel 5, the agitation device 6 and the entry point of two fluids 1 and 2 into the system;
30 Fig. 2 is an enlarged sectional view of jet chamber 3 showing an arrangement for impinging jet introduction of two fluids inta the system;
79/CSg28 - 11 - 18128IA
FzG. 3 is an overhead view of the jet chamber 3;
~'I~. 4 shows particle surface area as a function of supersaturation ratio using the jet crystallization process with simvastatin; and FIG. 5 is a schematic diagram showing a crystal production system depicting two fluids, 11 and 12, entering directly into the stirred vessel 13 containing liquid 14 (the liquid being solvent and/or anti°solvent) where the jets 16 emit fluid jetstreams that impinge and micromix near the effluent stream of the impeller 15.
~n n~SC~z~TZO~a of TH~ zrrv~rrTZO~
The novel process of this invention involves the use of jets to create impinging fluid jet streams and thereby achieve high intensity micaomixing of the fluids prior to nucleation in a crystallization process. Two or more jets may be used to micromix two or more fluids. Preferably, two jets are used to micromix two fluids. 6~hen using two jets, preferably the two impinging jet streams should be substantially diametrically opposed to each other, i.e., they should be at or close to a 180 degree angle to each other from an overhead view. FTG. 1 shows one ennbodiment of this invention wherein two jets are employed; fluids 1 ~a~d 2 enter the jet chamber 3 where micromixing takes place. F'IC 5, shows another embodiment of this invention, wherein ~
jets are employed and the jetstreams impinge and F~
~a/csQzs - 12 - 18x2~zA
micromi~c directly in the stirred vessel 13. As used herein, the terms stirred vessel and age vessel have the same meaning and axe interchangeable.
The two fluids used in the novel process of this invention can be of different solvent composition, one fluid being a solution of the compound to be crystallized in a suitable solvent or combination of solvents ('°feed solution"), and 'the other fluid being a suitable solvent or combination of solvents capable of initiating that compound's precipitation from solution ('°anti-solvent"), chosen for its relatively low solvation property with respect to that compound. Such solvents and anti-solvents can include but are not limited to methanol, ethyl acetate, halogenated solvents such as methylene chloride, acetonitrile, acetic acid, hexanes, ethers, and water.
Or, the two fluids used in the process can both be solutions of the compound to be crystallized 2o in the same suitable solvent or combination of solvents but each at a different temperature, and nucleation/precipitation can be initiated by instantaneous temperature reduction. The temperature and composition of each solution are chosen so that 1) no material will crystallize upstream of the impinging jets, and 2) sufficient supersaturation will be developed in the impinging jets to cause nucleation. ~Iicrom~.~ing creates temperature and compositional uniformity throughout the mixture prior to the start of nucleation.
The following is a list of compounds that have been successfully crystallized to meet particle size and purit=y specifications using the present invention: simvastatin, lovastatin (crude and pure), Proscar (Trade-mark for finasteride containing pharmaceutical composition) diltiazem malate, 173-benzoyl-4-aza-5a-androst-1-ene-3-one, 4"-epi--ac etylamino-avermectin B1, [trans-(-)]-2-[(3-methoxy-2-propoxy-5-- [tetrahydro-5- (3, 4, 5-trimethoxyphenyl) -2-furanyl] phenyl] -sulfonyl] -ethanol (DevLab, England) . However, this is not. an exhaustive list of all the compounds that can be used with the present invention.
After micromixang in a jet chamber, the material leaves the jet chamber as depicted in Fig. 1, travels into a stirred vessel 5 either directly or via a transfer lane 4, and after an appropriate age time, the product suspension flows out of the vessel as indicated by arrow A. Another embodiment of this invention involves the micromixing of two impinging jetstreams directly in the stirred vessel without the use of a jet chamber or transfer line, as depicted in FIG. 5. For the crystal-lization of simvastatin, the preferred method is for two jetstreams to impinge directly in the starred vessel. Once the material leaves the stirred vessel, appropriate recovery techniquE>_s are used to isolate the product crystals. The material preferably flows through the system in a continuous process, although it is possible to hold up the process in a batchwise fashion at the stirred vessel-aging step given a vessel of sufficient volume.
As shown in FIG. 2 and FIG. 3, the jet chamber 3 is preferably cylindrical in shape and as shown in FIG. 2 the jet chamber 3 preferably has a floor l0 which slopes downward in a conical shape toward the flooros center which is open to a connecting transfer line 4 or directly into a stirred vessel or other appropriate container. The diameter and cylinder wall height of the chamber can vary according to scale needs.
Regardless of the number of jets used, the jet nozzles should be placed so that the fluid streams they emit will impinge, either inside the jet chamber ox directly in the stirred vessel. The fluid jets must impinge to create an immediate high turbulence impact; concentric or converging jets generally create insufficient turbulence to achieve the required micromixing. When two jets are used with a jet chamber, as shown in PTG. 2 and PIG. 3, the two jet nozzles 7 are preferably arranged so that they are substantially diametrically opposed to each other with their outlet taps directed to face each other; i.e., the two jet nozzles are at or close 'to a 18~ degree angle to each other from an overhead view. Preferably, each jet outlet nozzle can have a slight downward angle from the horizontal of about 1Q
degrees to help the flowing material move down and out of the chamber.
~5 hikewise, two jet nozzles placed directly inside the stirred vessel are preferably arranged so that they are substantially diametrically opposed to each other with their outlet tips directed to fat's each other. When the jet nozzles are so placed, each nozzle can have a slight upward or downward angle from the horizontal of from 0 degrees up to about 15 degrees, but preferably the two nozzles have just a~~~~
enough downward angle from the horizontal (~. 13 degrees) to ensure that the fluid stream of one will not enter the outlet hole of the opposite nozzle.
One jet nozzle is used to transport one of the two fluids from an external source into the chamber and the other jet is used to similarly transport the other fluid. The distance between the nozzle tips inside the jet chamber or stirred vessel should be such that the hydrodynamic form of each a0 fluid jet stream remains essentially intact up to the point of impingement. Therefore, the maximum distance between the nozzle tips wall vary depending on the linear velocity of the fluids inside the jet nozzles. To obtain good results for generally non-viscous fluids, linear velocity in the jet nozzles should be at least about 5 meters/sec., more preferably above 10 meters/sec., and most preferably between about 20 to 25 meters/sec., although the upper limit of linear velocity is only limited by the practical difficulties involved in achieving i~t.
Linear velocity and flow rate can both be controlled by various known methods, such as altering the diameter of the entry tube 8 and/or that of the nozzle outlet tip 9, and/or varying the strength of the external force that moves the fluid into and through the nozzle. Each jet apparatus can be manipulated independently to attain a desired final fluid composition ratio. 4Jhen the desired flow ratio of one jet to the other differs from unity, preferably the difference is compensated for by appropriate sizing of the entry tubes. For example, if a 4:1 volumetric ratio of feed solution to 1~
'79/C5Q28 -- 16 - 18128I~
anti-solvent is desired, the entry tube delivering feed solution should be twice the diameter of the entry tube delivering anti-solvent. tdhen the jetstreams impinge inside a jet chamber, residence time for the fluid inside the jet chamber is typically very short, i.e., less than ten seconds.
A transfer line 4 as shown in FIG. 1 may or may not be used to deliver the fluid mixture into a stirred vessel 5 from the jet chamber. Solvent, anti--solvent or mixtures thereof optionally containing seed and optionally heated to attain optimum crystallization results can be put inside the stirred vessel FIG. 1 (5), FIG. 5 (13) at the start of the process before the micromixed fluids enter the stirred vessel; this technique is especially preferred when the jetstreams impinge directly in the stirred vessel. Crystal digestion (ostwald ripening, improvement of surface structure) tales place inside the stirred vessel.
2o Stirring in the vessel is provided by standard agitators 6, preferably Rushton turbines, Intermig impellers, or other agitators suitable for stirring a slurry suspension. Any impeller providing good circulation inside the vessel may be used.
Rowever, when the jetstreams are arranged to impinge directly inside the stirred vessel, an agitator that does not interfere with the space occupied by the impinging jetstreams inside the vessel is preferred, especially, e.g., a Rushton turbine. As depicted in 3o FIG. 5, impinging jetstreams inside the vessel are most preferably placed in the effluent stream of the agitator, and the height of the liquid in the stirred vessel when operated in continuous mode (i.e., flow in equals flow out, constant volume maintained), is most preferably between about two to four times the height of tlZe impeller.
The crystalliz<~tion is preferably run in a con-t:inuous process and the appropriate residence time for the completion of crystal digestion is attained by adjusting the volume capacity of the stirred vessel, but the mixture can be held up in the vessel for any desired length of age time if batchwise processing is desired.
For example, during simvastatin crystallization crystal digestion is complete within about 5 minutes and a vessel volume of roughly 5 liters is sufficient for a residence t=ime of 5 minutes with a material flow of about 1 liter per minute. Finasteride (Proscar) is similar to simvastatin with respect to age time. In some instances when the fluids impinge and micromix inside a jet chamber, crystallization conditions may be optimized so that crystal precipitation and growth are completed w=ithin the transfer line itself, or even before entering the transfer line, and the crystals may be directly collected, bypassing any age time in the stirred vessel.
Manual seeding can be done at any point in the system, e.g., in the stirred-vessel, the transfer line or the jet chamber itself. In some situations" the continuous jet process may be "self-seeding", i.e., the first crystals to form inside the jet chamber (if used), the transfer line (if used) or the stirred vessel (if used) serve as seed for the material that flows through thereafter.
P
The micromixed material must be highly supersaturated to attain the beneficial results of the jet crystallization process. Aside from thermoregulated initiation of nucleation, temperature variation also affects product results when anti-solvent is used to initiate nucleation because of its effect on supersaturation. Generally, good results can be achieved for pharmaceutical compounds using a volumetric ratio of feed solution to la anti-solvent that pravides a high degree of supersatuzation in the jet chamber in a temperature range of about 24°C to 70°C, although temperature height is limited only by the chosen solvent's boiling point and the compound's decomposition range. Temperatures above ambient may give improved product characteristics. As an exacnple, optimum results with regard to end product ~>urface area, purity and stability are achieved for simvastatin by xunning the crystallization at an e7levated 2~ temperature of at least 55°C, more preferably in the range of 60 to 70°C, and most preferably at 65 to 68°C, in a 41:59 volumetric mixture of Me0H:H2Q. In this case, the composition in the impinging jetstreams is 50:50 Me0H:H2a, and the composition in 2~ the age 'tank is brought to 41:59 MedH:H~O by a separate, additional water injection (nat through the impinging jet) directly into the stirred vessel. ~
75:25 volumetric mixture of Me0H:H20 used at room temperature produces crystals essentially the same as those from conventional batchwise crystallization, i.e, they require milling. A 41:59 volumetric mi~cture of Me0H:H20 used at room temperature results in particles with average surface area above the desirable range and decreased purity as shown in FIG. 4.
Ambient temperature (room temperature) operation using the jet process provides sufficiently good re:~ults for finasteride (Proscar) and therefore elevated temperatures are not necessary.
A temperature of 40 to 58°C using the jet process is suitable for lovastatin.
The following examples are given for the purpose of illustrating the present invention and should not be construed as limitations on the scope or spirit of t:he instant invention.
EXAMPLE I
Crystallization of Einasteride (Proscar) 100 Grams of Proscar was dissolved in 600 ml. of glacial acetic acid; once dissolution was complete, 400 ml.
deionized water was added (i.e., a 60:40 volumetric ratio of glacial acetic acid: water). The solution was filtered a;~ 1 litre of feed solution through a 0.2 micron membrane into a blow can. The blow can outlet was connected to a 1/16 in. OD jet nozzle (0.052 in. ID). 5.5 Liters of deionized water was filtered as anti-solvent througr, a 0.2 micron membrane into a second blow can, and its outlet connected to a 1/8 in. OD jet nozzle (0.0938 in.
ID). This provides a 1:5.5 volumetric ratio of feed solution:anti-solvent. Each blow can was pressurized to - 19a -ca. 90 psi with regulated nitrogen. The impinging jets were started simultaneously. The desired flow rate of the acetic acid solution was 0.2 gpm (linear velocity ca. 550 meters/min:) and the desired flow rate of 100% H20 was 1.1 gpm (linear velocity ca. 930 meters/min.). The effluent slurry was collected from the mixing chamber in a 12L
round-bottom flask equipped with a paddle agitator. A
minimum age time of two minutes was required to complete crystal digestion. 'rhe solids were filtered, water washed, then dried.
Crystals were 10 to 20 microns in diameter and 1 micron thick, in the form of flakes; specification is 950 <:
smaller than 25 microns.
Crystallization of Simvastatin 100 Grams of s:imvastatin were dissolved in 1400 ml.
methanol, and the solution heated to approximately 550C.
Deionized water (1400 ml.) was heated to approximately 55°C. The heated water was fed to one blow can and the heated methanol solution was fed to a second blow ca.n.
Each blow can outlet was connected to a lmm. ID jet nozzle. Each blow can was pressurized to 25-35 psi, and impinging jets were started simultaneously. The flow from each jet was 1.1 liter/min. (linear velocity ca. 23 meters/sec.).
The jet chamber was approximately 2 inches in diameter and I inch high with a conical bottom outlet. Effluent from this chamber was directed to a 4 liter beaker (approx. 6 inches diameter). The beaker contained 2.5 grams simvastatin seed (dry surface area 2.5 to 6 sq:
m/gm), and was agitated at 300 "M by three Ekato Intermig (Trade-mark) impel:Lers, each 3.5 inches in diameter. When the cans were empty (75 seconds), they were vented. Aging (agitation at 300 RPM, no cooling) took place in the beaker for 5 to 20 minutes. The contents were then cooled with the ;~~~'~'~~~
same agitation to less than 30°C by immersion in an ice bath. Contents were then filtered and tray dried (~0°C at 28-30 in. Eg vacuum with slight nitrogen sweep) for 12 to 16 hours.
The resultant dry solid (88-99 grams) had a surface area of 3.1 ~/° 0.~ square meters per gram. Mother liquor losses were 1-2°~, the remaining yield being held up in the apparatus. product could be used to seed future batches without further 1~ treatment.
~XAI~IpLE ~ , Crvstallizati~n c~f 'mv statin, 68-68°C
The crystallization of example 2, with the following modifications:
(1) temperature in the jet impingement zone and in the 5 to 20 minute age was raised to 86-68°C, 2~ by preheating the methanol feed solution to 55°C and the water feed to 85°C; and (2) final age tank solvent composition was reduced to 41°/ methanol by suspension of the initial 2W gram seed charge in 600 m1 deionized water at 70°C.
the final product was similar in particle size, surface area and appearance to the product from sample 2. aowever; storage stability (60°C) was improved from very good (F~cample 2) to outstanding (Example 3), implying a higher order of crystallinity.
Crystallization of.-Simvastatin, Immersed jets The crystallization of Example 3, with the modification that the impinging jets-were submerged,.
without containment, inside the agitated age vessel near the effluent stream of the impeller. To accommodate the immersed jets, a 6-liter baffled battery jar (cylindrical), 8-1/4 inches in diameter and 10 inches high, was agitated by a 3 inch diameter Rushton turbine.
T:he impinging jets were located near the horizontal plane of the impeller, I to 2 inches from the impeller's outer edge.
The final product was essentially identical with that of Example 3. Caking of amorphous solid on the wall of the jet chamber, which occurs in extended runs in Examples 2 and 3, was eliminated because there was no containment wall around the jets.
Crystallization of Lovastatin 38.0 Grams of lovastatin were added to 1260 ml methanol and 140 ml deionized water (i.e. 90:10 volumetric ratio o:f methanol t.o water). The mixture was heated to 55°C with agitation (magnetic stirrer in closed Erlenmeyer flask). Activated carbon (12.78, Calgon type APA 12x40 - Calgon .is a Trade-mark) was added, the mixture stirred at 55°C and hot filtered. The filtrate was reheated to 55°C (when necessary) and added quickly to a blow can attached to one impinging jet device nozzle (1.0 mm diameter) as feed solution. 538 Milliliters of 60°C deionized water (anti-solvent) was added to another blow can connected to the opposing jet (0.5 mm diameter). Both cans were pressurized to 25-30 psig and the liquids fed to the respective jets, completed in 1 minute, 45 seconds (i.e., a 2.6:1 volumetric ratio of feed solution:anti-solvent). The agitated beaker (same as Example 1) was aged at the jet outlet temperature (43°C) for 5 minutes, cooled with stirring to less than 30°C, and filtered and dried.
The final product was fine needles with acceptable surface area 1.6m2/gm. Purity was equal to that from.
conventional seeded crystallization.
Claims (18)
1. A process for crystallization of an organic pharmaceutical compound comprising high intensity micromixing of fluids by means of jets that create impinging fluid jet streams of the component fluids, wherein at least one of the fluids is a solution of the compound to be crystallized, which causes formation of a homogeneous supersaturated fluid composition prior to the start of nucleation, nucleating crystals of said compound in said supersaturated composition, and recovering crystals of said organic pharmaceutical compound.
2. The process of Claim 1 wherein two jets are used and the two impinging jet streams are substantially diametrically opposed to each other, and the hydrodynamic form of each fluid jet stream remains essentially intact up to the point of impingement.
3. The process of Claim 1 or 2 wherein super-saturation is accomplished by using an anti-solvent, or by instantaneous temperature reduction or by a combination of both.
4. The process of Claim 3 wherein the temperature of the fluids to be micromixed is between 24-70°C.
5. The process of Claim 4 wherein the crystallization is a continuous process.
6. The process of Claim 5 wherein the linear velocity of the fluid jets inside their respective jet nozzles is at least about 5 meters/sec.
7. The process of Claim 6 wherein the linear velocity is greater than 10 meters/sec.
8. The process of Claim 7 wherein the linear velocity is between about 20-25 meters/sec.
9. The process of Claim 7 wherein the compound to be crystallized is finasteride and the process is conducted at room temperature.
10. The process of Claim 9 wherein the feed solution is comprised of finasteride dissolved in a 60:40 volumetric ratio of glacial acetic acid:water, the anti-solvent is comprised of 100% water, and a 1:5.5 volumetric ratio of feed solution: anti-solvent is used.
11. The process of Claim 8 wherein the compound to be crystallized is simvastatin, and the process is conducted in a temperature range of about 55-70°C.
12. The process of Claim 11 wherein the feed solution is comprised of simvastatin dissolved in 100%
methanol, and supersaturation is accomplished with an anti-solvent comprised of 100% water, and a 41:59 volumetric ratio of feed solution: anti-solvent is used.
methanol, and supersaturation is accomplished with an anti-solvent comprised of 100% water, and a 41:59 volumetric ratio of feed solution: anti-solvent is used.
13. The process of Claim 12 wherein the temperature is between 60-70°C.
14. The process of Claim 13 wherein the temperature is between 65-68°C.
15. The process of Claim 8 wherein the compound to be crystallized is lovastatin, and the process is conducted in a temperature range of about 40-58°C.
16. The process of Claim 15 wherein the feed solution is comprised of lovastatin dissolved in a 90:10 volumetric ratio of methanol:water, the anti-solvent is comprised of 100% water, and about a 2.6:1 volumetric ratio of feed solution to anti-solvent is used.
17. The process of any one of claims 1 to 16 wherein the jet streams are directed from jet nozzles into a jet chamber, and each jet nozzle has a downward angle from the horizontal of about .10°.
18. The process of any one of claims 1 to 16 wherein the jet streams are directed from jet nozzles into a stirred vessel and the nozzles are at or close to the horizontal plane or are at a downward angle of up to about 15 degrees below the horizontal plane, and positioned so that the fluid jetstreams they emit will be in an effluent stream of an impeller of the stirred vessel.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US53861190A | 1990-06-15 | 1990-06-15 | |
| US538,611 | 1990-06-15 | ||
| US70668291A | 1991-06-03 | 1991-06-03 | |
| US706,682 | 1991-06-03 |
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| CA2044706A1 CA2044706A1 (en) | 1991-12-16 |
| CA2044706C true CA2044706C (en) | 2003-02-25 |
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|---|---|---|---|
| CA 2044706 Expired - Lifetime CA2044706C (en) | 1990-06-15 | 1991-06-14 | Crystallization method to improve crystal structure and size |
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| EP (1) | EP0461930B1 (en) |
| JP (1) | JP3282731B2 (en) |
| CA (1) | CA2044706C (en) |
| DE (1) | DE69112917T2 (en) |
| ES (1) | ES2078447T3 (en) |
| IE (1) | IE67187B1 (en) |
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-
1991
- 1991-06-14 JP JP14325991A patent/JP3282731B2/en not_active Expired - Fee Related
- 1991-06-14 IE IE204491A patent/IE67187B1/en not_active IP Right Cessation
- 1991-06-14 CA CA 2044706 patent/CA2044706C/en not_active Expired - Lifetime
- 1991-06-14 DE DE69112917T patent/DE69112917T2/en not_active Expired - Fee Related
- 1991-06-14 EP EP19910305432 patent/EP0461930B1/en not_active Expired - Lifetime
- 1991-06-14 ES ES91305432T patent/ES2078447T3/en not_active Expired - Lifetime
- 1991-11-18 US US07/793,764 patent/US5314506A/en not_active Expired - Lifetime
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| DE69112917D1 (en) | 1995-10-19 |
| US5314506A (en) | 1994-05-24 |
| IE912044A1 (en) | 1991-12-18 |
| CA2044706A1 (en) | 1991-12-16 |
| EP0461930B1 (en) | 1995-09-13 |
| DE69112917T2 (en) | 1996-05-15 |
| IE67187B1 (en) | 1996-03-06 |
| EP0461930A1 (en) | 1991-12-18 |
| JPH04231960A (en) | 1992-08-20 |
| JP3282731B2 (en) | 2002-05-20 |
| ES2078447T3 (en) | 1995-12-16 |
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